Micro RNA (miRNA) are short endogenous ribonucleic acid molecules that participate in the regulation of gene expression. miR-323-3p is a 21 nucleotide long regulatory microRNA (SEQ ID 1: CAC AUU ACA CGG UCG ACC UCU) which is derived from the 3′ end of the precursor stem loop pre-miR-323 (SEQ ID 2: UUGGUACUUG GAGAGAGGUG GUCCGUGGCG CGUUCGCUUU AUUUAUGGCG CACAUUACAC GGUCGACCUC UUUGCAGUAU CUAAUC).
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease ultimately leading to joint destruction and disability. The invasion of synovial cells into articular cartilage and bone contributes significantly to joint destruction in RA. Activated synovial fibro-blasts (SF) are involved in this process. They attach to the cartilage surface and release matrix-degrading enzymes, importantly among them matrix metalloproteinases. Overexpression of tissue inhibitors of metalloproteinases (TIMPs) has been shown to reduce invasiveness of RA synovial fibroblasts (RASF) and inhibit their proliferation (van der Laan et al. 2003, Gene Therapy 10, 234-242).
Currently available medication for RA is aimed at slowing the disease progression and alleviating symptoms, but no curative treatment is available. Hence, the objective of the present invention is to provide safe and efficacious means for the prevention and treatment of rheumatoid arthritis. This objective is attained by the subject-matter of the independent claims.
The central feature of the invention is the surprising finding that miR-323-3p is significantly increased in rheumatoid arthritis and thereby involved in the up-regulation of pro-inflammatory cytokines and matrix metalloproteinases in synovial fibroblasts from patients with rheumatoid arthritis (RASF). miR-323-3p also potentiates cell migration, proliferation and adhesion, other key processes in the pathogenesis of RA. Furthermore, TIMP-3, which inhibits invasion of RASF in the cartilage (van der Laan, ibid.), is a direct target of miR-323-3p. The miRDB database accessible at mirdb.org lists 371 predicted targets for miR-323-3p on 30 Aug. 2011; no member of the TIMP family of proteins is among them.